Abstract: Peripheral neuropathy is one of the major common complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function caused by diabetic peripheral neuropathy. Exosomes, endosome-derived nano vesicles carry proteins and RNAs as their molecular cargo. Exosomes mediate intercellular communication by transferring their cargo between source and target cells. Exosomes are presently in clinical trials for treatment of type 1 diabetes, cutaneous wound healing and several cancers. However, the effects of Schwann cell-derived exosomes as a treatment of diabetic peripheral neuropathy have not been investigated. In a novel set of experiments, our preliminary data show that intravenous administration of Schwann cell-exosomes remarkably improves sciatic nerve neurovascular function and peripheral nerve function in diabetic mice, indicating that exosomes have a beneficial effect on the treatment of diabetic peripheral neuropathy. In this application, we therefore propose to investigate the mechanisms underlying the therapeutic effects of Schwann cell-exosomes on diabetic peripheral neuropathy, with a focus on neurovascular remodeling. Our hypotheses are: 1) Treatment of diabetic peripheral neuropathy with Schwann cell-exosomes improves neurological outcome in mice with diabetic peripheral neuropathy by transferring exosomal microRNA (miR)-9, -21, and -27a into the sciatic nerves of dorsal root ganglion (DRG) neurons, Schwann cells, and endothelial cells, leading to suppression of their target proteins, SEMA6A, RhoA, PTEN and pNF-?B. And 2) Treatment of diabetic peripheral neuropathy with engineered exosomes carrying elevated miR-9, -21, and -27a enhances neurovascular function and improves neurological outcome compared to nave-Schwann cell-exosome treatment. The effect of the exosomes on expression of miR-9, -21, and -27a and their target proteins SEMA6A, RhoA, PTEN and pNF-?B in the sciatic nerve of the DRG neurons, Schwann cells, and endothelial cells will be examined. The neurovascular function and neurological outcomes will be measured. These studies are innovative and will provide new insight into mechanisms underlying the neurological dysfunction of diabetic peripheral neuropathy, and may lead to the development of a new treatment using Schwann cell-exosomes. Relevance Statement: Diabetic peripheral neuropathy is a major disability affecting millions of Americans. In this proposal, employing preclinical studies in the diabetic animal, I seek to develop a novel treatment for diabetic peripheral neuropathy using exosomes derived from Schwann cells. In this proposal, I will also elucidate the molecular mechanism by which exosomes are therapeutically effective. This research will provide the essential pre-clinical data for translation to a phase 1 clinical trial.